Stereoselective Diels–Alder Reactions of gem-Diborylalkenes: Toward the Synthesis of gem-Diboron-Based Polymers

Although gem-diborylalkenes are known to be among the most valuable reagents in modern organic synthesis, providing a rapid access to a wide array of transformations, including the construction of C–C and C-heteroatom bonds, their use as dienophile-reactive groups has been rare. Herein we report the Diels–Alder (DA) reaction of (unsymmetrical) gem-diborylalkenes. These reactions provide a general and efficient method for the stereoselective conversion of gem-diborylalkenes to rapidly access 1,1-bisborylcyclohexenes. Using the same DA reaction manifold with borylated-dienes and gem-diborylalkenes, we also developed a concise, highly regioselective synthesis of 1,1,2-tris- and 1,1,3,4-tetrakis(boronates)cyclohexenes, a family of compounds that currently lack efficient synthetic access. Furthermore, DFT calculations provided insight into the underlying factors that control the chemo-, regio-, and stereoselectivity of these DA reactions. This method also provides stereodivergent syntheses of gem-diborylnorbornenes. The utility of the gem-diborylnorbornene building blocks was demonstrated by ring-opening metathesis polymerization (ROMP), providing a highly modular approach to the first synthesis of the gem-diboron-based polymers. Additionally, these polymers have been successfully submitted to postpolymerization modification reactions. Given its simplicity and versatility, we believe that this novel DA and ROMP approach holds great promise for organoboron synthesis as well as organoboron-based polymers and that it will result in more novel transformations in both academic and industrial research.


■ INTRODUCTION
Organoboron reagents have had an enormous impact on the development of new chemical reactions 1 and have extended the scope of accessible complex molecular scaffolds. 2−4 Organoboronate compounds are particularly attractive owing to their wide availability and air stability, 5 making them versatile reagents in organic synthesis. 6,7 Although many synthetic methods utilize transformations of C−B bonds, 2 the development of polyborylated reagents would enable greater structural diversity, an important objective. 8 Therefore, over the past decade, much effort has been expended to synthesize new functionalized classes of polyboronates, which have been shown to be excellent building blocks for the modular construction of new compounds. 9−12 Among polyboron-containing structural motifs, (unsymmetrical) 13 gem-diboron derivatives (2, 3′) are a well-known emerging class with good potential for novel synthetic applications ( Figure 1A). 14−17 The special properties and structures of bisnucleophile gem-diboryl compounds 2 and 3′ (termed geminated organodimetallics) 18,19 have attracted increasing attention from synthetic chemists, particularly in constructing C−C/C−heteroatom bonds. In recent years, gemdiboryl compounds 2 and 3′ have been widely adopted as coupling partners in synthetic chemistry. 11,20 For example, gem-diborylalkenes 2 have served as building blocks for Suzuki−Miyaura cross-coupling, nucleophilic partners, reduc- tion approaches, Michael additions, 21 radical chemistry, 22 and other reactions. 13,23 Despite the fact that organoborons 1 and 1′ ( Figure 1A) have been applied in many fields including materials, polymer 24−29 I ( Figure 1B), drugs, 30 and, in industry, gemdiboryl units 2 and 3′ have seldom been employed in these fields, e.g., polymer II ( Figure 1C). 30 To this end, we contend that a new paradigm of research is needed to complementarily propel this gem-diboryl class of compounds to reach the same application level as their monoboron analogues.
As a part of a general program to investigate the reactivity and selectivity of gem-diboryl compounds in new synthetic applications, we sought to prepare variants bearing the gemdiboryl-norbornene group (4) because these strained compounds (∼27 kcal/mol of inherent strain) might offer new opportunities toward the ring-opening metathesis polymerization (ROMP) reaction 31 and lead to unprecedented gemdiboryl-based polymer II′ ( Figure 1D).

■ RESULTS AND DISCUSSION
We posited that an efficient way to prepare gem-diborylnorbornene structural motifs 4 would be through a [4 + 2] cycloaddition reaction of gem-diborylalkenes 2 with cyclopentadiene (CP) 3. Although the [4 + 2] cycloaddition reactions of vinylboranates, 32 e.g., 1, are well documented in the literature (Figure 2A), 33−36 to the best of our knowledge, the use of gem-diborylkenes 2 in these types of reactions is rare, 23 despite the potential to provide new and efficient strategies to efficiently construct complex molecules ( Figure  2B). 34,36 Recently, we reported a photoredox-mediated reaction of gem-diborylalkenes 22 and showed that gem-diborylalkenes 2 have similar electron deficiency as vinylboron 1; 22 hence, 2 should serve as a suitable dienophile for this type of cycloaddition reaction. However, key challenges include (1) the steric repulsion introduced by the two groups of the bulky Bpin units in the TS of the cycloaddition reaction; 37 (2) whether the regio-and stereoselectivity of the cycloaddition can be controlled when two unsymmetrical boron groups are placed on the geminated carbon of dienophile 2′; 13 and (3) whether the reaction can proceed in a regioselective manner when borylated dienes react with 2 ( Figure 2B). 34 To answer these questions, we first conducted computational studies on the Diels−Alder (DA) reaction to predict whether gem-diborylalkenes 2 could be used as dienophile reactive partners for the DA reaction. 35,38 According to our computational studies of the energy profiles of the cycloaddition reactions of diene-Cp 3e with dienophiles 1 and 2 at room temperature (rt), the transition state of gemBpinBpin-TS is likely to be more energetically stabilized compared to vinyboronate TS Bpin-exo-TS by 1.4 kcal/mol ( Figure 2C,D). Considerations for the relative stabilities of the different transition states are discussed in the SI (pp S65, S66). 36,38,39 Moreover, the CHelpG population analysis 40 on the carbons of the reactive double bond of the dienophiles (1 and 2) shows that the double bond of 2 has less electron concentration than the double bond in 1 (full details are given in the SI (pp S65, S66). These observations support the fact that 2 is slightly more "dienophilic" toward the DA reaction than 1, albeit more bulky ( Figure 2C,D).
To investigate our proposed reaction, gem-diborylalkene 2, along with 3e, was subjected to DA reaction conditions ( Figures 2C-2, 3A,B). We obtained the desired gemdiborylated cycloaddition product 4e in good yield at rt with toluene as solvent. Next, we investigated the scope of the DA reaction using readily available gem-diborylalkene 2 and various diene substrates (3) bearing aliphatic, aromatic, and heteroatom substituents ( Figure 3B). Generally, the products (4a−g) were isolated in good yields under the established optimal conditions. The reaction also proceeded in very good yield on a gram scale, e.g., 4e. The reaction works well with anthracene derivative 3c, affording the gem-diborylcyclic adduct 4c, which was confirmed by X-ray crystallographic analysis (see the CYLview structure of 4c, Figure 3B). In addition, the reaction works smoothly with hexachlorocyclopentadiene 3e-6Cl, forging the hexachloro cycloaddition product 4e-Cl.
The reaction also exhibits moderate regioselectivity when unsymmetrical dienes are used, giving the para adducts (4h−j, Figure 3C). Notably, the constitutional isomers in 4 (h, h′) and 4 (i, i′) can be easily separated by column chromatography ( Figure 3C; see the SI).
Next, the polyborylated cycloadducts 4 were subjected to oxidation reactions using H 2 O 2 ( Figure 4). 45 Oxygenated compounds 4O were obtained in a chemoselective manner ( Figure 4). Thus, we have demonstrated that gem-diborylalkenes serve as ketene equivalents in [4 + 2] cycloadditions. 46 Of note, 4d has been subjected to two oxidation reactions that lead chemoselectively to two different products, 4O-d and 4O-d′. In 4O-d, first the double bond was stereoselectively epoxidized and then the gem-di-Bpin unit underwent oxidation. However, in 4O-d′ the geminal-Bpin position first underwent oxidation and then the double bond isomerizes due to the deprotonation of the acidic benzylic and allylic proton that is located α to the generated carbonyl ( Figure 4; see proposed pathways in the SI). When triboryl compound 4k was subjected to the oxidation conditions, ketone 4O-k was selectively obtained, most likely resulting from oxidation of the gem-diboryl moiety to give a boronenolate, 47 which hydrolyzed in situ to finally give 4O-k ( Figure  4; see proposed pathways in the SI).
Furthermore, we investigated the DA reaction using unsymmetrical 1,1-bisdiborylalkenes (2′ and 2-F). It was anticipated that the cycloaddition might proceed with good stereoselectivity ( Figure 5). 13 We were happy to discover that the reaction of 1,1-BpinBdan-ethene (2′) with dienes 3a−d afforded the unsymmetrical gem-diborylalkane 5a−d (confirmed by X-ray crystallographic analyses of 5a and 5c) in good yield ( Figure 5A,B). High diastereoselectivity was observed in the reaction of 2′ with CP, affording cycloaddition product 5c (endo:exo = 92:8). Our calculations indicate that the reaction favors the endo product 5c with the TS energy of endo-BpinBdan-TS, which is 2 kcal/mol less than that of exo-BpinBdan-TS ( Figure 5C). 24,35,38 This is in good agreement with the fact that the aromatic-planar Bdan group is less bulky than the Bpin group. 13,33,37,48 Therefore, it would appear that the diastereoselectivity in this case is driven primarily by sterics (additional considerations for the relative stabilities of the different transition states are discussed in the SI (pp S65, S66)).
Moreover, the reaction of 2′ with 3,4-diboryl diene 3l yielded 1,1,3,4-tetraborylcyclohexene adduct 5l ( Figure 5D). Additionally, the DA reaction of 1-boron-diene 34,43 (E-3k) with gem-diborylalkene 2′ generated regioselectively the separable diastereomers of the 1,1,2-triboryl cyclic adduct with complete stereospecificity (5k, 5k′; Figure 5E). 43, 44 We have obtained unambiguous support for the structures of 5k′ using X-ray crystallographic analysis (see CYLviews in Figure  5E). These two different boron groups can provide the basis for selective C−B sequential functionalization, which in turn reacts differently. 13,49 Unlike boronic esters, for example, the Bpin and Bdan groups, monoalkyl-trifluoroborate salts are known to be easily activated and to undergo rapid transmetalation with transitionmetal complexes. In general, owing to their air, moisture, shelf, and thermal stability, as well as their occurrence as free-flowing crystalline solids, monotrifluoroborate salts have now become extremely popular reagents in synthesis. Thus, we attempted to use the gem-BpinBF 3 Cs alkene 2-F as a dienophile for the DA reaction ( Figure 6A). Unfortunately, the reaction did not afford the desired product (gem-diborylcyclohexene BF 3 Cs containing 6) and instead led to decomposition ( Figure 6A). Alternatively, we sought to obtain product 6 using our recently reported conditions for late-stage trifluoroboration of gemdiborylalkenes by employing CsF (Figure 6B,C). 50 We were pleased to observe the desired mono-BF 3 Cs products 6a−d in good yield ( Figure 6C). Moreover, the reaction shows moderate diastereoselectivity in 6b and 6d when 4e and 4g, respectively, are used. The rationale of the diastereoselectivity is in good agreement with our reported mechanism that follows the likelihood that fluorination occurs from the less sterically encumbered face of norbornenes 4e−g, affording the exo-disposed BF 3 Cs group (6b and 6d, respectively). 50 Next, we envisioned a stereodivergent synthesis of norbornene 5f involving controlling exo and endo norbornene structural motifs as illustrated in Figure 7. Toward this goal, cyclopentadienyl 3f was reacted in two different scenarios. In path a (Figure 7), 3f reacted with the unsymmetrical gemdiborylalkene 2′ to form only the cycloaddition product 5fendo (confirmed by X-ray) in 85% yield. In path b (Figure 7), 3f was first reacted with the symmetrical gem-BpinBpin-alkene 2 to yield 4f as a single diastereomer, which was then subjected to a diastereoselective trifluoroboration favoring the less sterically hindered face of the norbornene (denoted by arrows in 4f) to afford 6f in high diastereoselectivity (94:06; Figure  7). 50 Finally, the BF 3 Cs group was converted to the Bdan group to afford the 5f-exo product (Figure 7). 50 Overall, our method serves as a powerful tool for the diastereocontrolled synthesis of norbornene motifs.
With these valuable gem-diborylcyclohexenes in hand, e.g., gem-diborylnorbornene, we sought to demonstrate their synthetic utility in selective transformations of the double bond through the ROMP reaction, as depicted in Figure 8A, to generate the novel gem-diborylalkene-based polymers. Organoboron polymers 29 have attracted widespread attention, since they provide unique properties for catalysis, sensory materials, luminescent materials, and biomedical applications. 26,27,29,30 Among them, polymers with pendant boronic acids/esters account for the majority, since boronic acids/ esters could serve as responsive sites of sensitive materials or dynamic cross-linking points of self-assembled polymers and self-healing materials. 26,27,30 Moreover, the presence of the boron moiety on the polymer offers a great opportunity for postpolymerization modifications 28,29 to achieve new functional groups that are difficult to achieve in regular polymerizations. 24,25,29 Although polymers that contain monoboron units have been widely used, 27 their gem-diboryl analogues have not been investigated; thus, they can provide a new array of polymer properties to forge a wider diversity of gem-diboron-based polymers. Thus, gem-diborylnorbornenes hold great promise to serve as a monomer for ROMP 31 reactions that form polymers containing gem-diboryl units ( Figure 8A). It is noteworthy that the ROMP reactions for the mono-boron-containing monomers are rarely reported, and there are only a few examples of very special side-chain boron groups. 51 In this regard, we chose the [Ru] Grubbs second-generation catalyst as a catalyst in the ROMP reactions, because its known to tolerate broad functional groups, air, and moisture, and this includes the fact that the Bpin group is expected to be intact under the Ru catalysis conditions for other types of reactions, i.e., olefin metathesis catalysts. 52 We subjected norbornenes 4e and 5c to ROMP 31 polymerization reaction conditions using 1 mol % of the [Ru] Grubbs second-generation catalyst and tetrahydrofuran (THF) as a solvent. 53 We were gratified to observe that gemdiborylnorbornene 4e and 5c selectively polymerized to afford, for the first time, gem-diboron-based polymers poly-7-BpinBpin and poly-7-BpinBdan, respectively, in high conversions ( Figure 8B). This transformation was followed by 1 H NMR spectroscopy of both monomers 4e and 5c and their corresponding polymers poly-7-BpinBpin and poly-7-BpinBdan, respectively, as depicted in the SI (pp S45−S49, S64). 25 The resulting polymer, poly-7-BpinBpin, was observed to have a light yellowish color; it has a high molecular weight (MW = 4.85 × 10 4 ) and polydispersity indexes (PDI) of M w / M n = 1.29, based on gel permeation chromatography (GPC) (Figure 8B,C). Furthermore, the polymer poly-7-BpinBdan was dark green and has a lower molecular weight (MW = 9.19 × 10 3 ) and a higher PDI of M w /M n = 1.61 ( Figure  8B,C). 24,25,31,39 Although these pristine polymers are expected to be colorless, the dark color of the poly-7-BpinBdan might be a result of the conjugated nature of the aromatic Bdan group. While both polymers have different MW values, the Figure 7. Stereodivergent synthesis of norbornene 5f. Path a: Norbornenediastereomer 5f-endo was stereoselectivity synthesized in one step from DA reaction of cyclopentadiene 3f with the unsymmetrical gem-diborylalkene 2′. The relative configuration of 5f-endo was determined using X-ray crystallography (see the CYLview structure of 5f-endo). Path b: 5f-exo was synthesized in three steps.
Step 2: stereoselective trifluorination of norbornene 4f from the less hindered si-face, leading to the exo product 6f.
Step 3: the gem-diborylnorbornene-BF 3 Cs 6f was directly converted to unsymmetrical gem-Bpin Bdan-norbornene 5fexo in a stereospecific manner. X-ray structures were visualized with CYLview 1.0b. 42   Journal of the American Chemical Society pubs.acs.org/JACS Article poly-7-BpinBpin is closer to the one expected at a 1 mol % catalyst compared with literature. 51 Subsequently, we examined the potential of postpolymerization modifications of these gem-diboron-based polymers by the functionalization of the double bond and the replacements of gem-diboryl units ( Figure 9A). These modifications include the hydrogenation of the ethylene moieties using p-toluenesulfonyl hydrazide 13 as a source for hydrogen ( Figure 9B). 54,55 The hydrogenation reactions proceed very efficiently for both gemdiboron-based polymers poly-7-BpinBpin and poly-7-BpinBdan to obtain the new hydrogenated polymers poly-8-BpinBpin and poly-8-BpinBdan, respectively, in a complete Journal of the American Chemical Society pubs.acs.org/JACS Article conversion ( Figure 9B). The hydrogenated polymers poly-8-BpinBpin and poly-8-BpinBdan were distinctly confirmed by 1 H and 13 C NMR spectroscopy (for full details see the SI). 55 Our efforts were also directed to the postpolymerization transformation of the boron groups through the selective replacement of one of the boron groups by trifluorination, 50 protodeborylation, 56 and deuterodeborylation 56 as described in Figure 9C. Remarkably, the trifluorination 50 reaction of polymer poly-7-BpinBpin represents an alternative method to the unsuccessful direct ROMP reaction of monomer Bpin-BF 3 Cs-norbornene 6b. Of note, these new polymers were confirmed by 1 H, D, 19 F, and 13 C NMR spectroscopy (for full details see the SI).
These preliminary postpolymerization transformations have demonstrated the utility of a replaceable-main-chain-based strategy using boron and the double bond as the key elements for opening new opportunities for the synthesis of a variety of new polymers.

■ SUMMARY
In conclusion, we have developed a method that addresses the long-standing challenge of regio-and stereoselective Diels− Alder cycloadditions with poly-alkenylboranes. This was achieved by introducing a new method that enables the use of (unsymmetrical) gem-diborylalkenes as a reasonable reactive dienophile for the DA reaction. The products of these reactions enable the formal synthesis of polyborylated cycloadducts, particularly the 1,1,2-tri-and 1,1,3,4-tetraborylcyclic adduct, which would be difficult to accomplish with the existing strategies. In addition, the reaction offers the stereodivergent synthesis of norbornenes by using a diastereoselective trifluorination reaction. We demonstrate the use of the gem-diborylalkenes as ketene equivalents in [4 + 2] cycloadditions. Moreover, we utilized gem-diborylnorbornene in the synthesis, for the first time, of gem-diboryl-based polymers through ROMP. These polymers underwent successful postpolymerization modifications to access new polymers, which also demonstrates the potential diversity of the main chain replacement. Studies to achieve an enantioselective DA transformation using chiral gem-diborylalkenes 33 as well as new postpolymerization transformations of gem-diborylcycloalkene-based polymers are currently under investigation and will be reported in due course.
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